JPH05255331A - MRSA active 2-halophenyl carbapenem - Google Patents

Abstract

PURPOSE: To obtain new 2-phenylcarbapenems that are useful for treating bacterial infections and have high level of anti-MRSA/MRCNS activities.

CONSTITUTION: The compounds of formula I [R is H or CH₃; R² is (R)-CH₃CH (OH)-, (R)-CH₃CH(F); M is a cation allowable for pharmaceuticals or ester; R^a is I or Br], for example, sodium (5R,6S)-2-[3-bromophenyl]-6-[(1R)- hydroxyethyl]-carbapen-2-em-3-carboxylate of formula II, which can be produced by reacting 3-bromophenyl magnesium bromide with (3S,4R)-1-[[(allyoxy) carbonyl](triphenylphosphoranylydene)methyl]-3-[(1R)-1-(allyoxycarboxyloxy) ethyl]-4-[(1R)-2'-[pyridylthio)carbonyl]methyl]azetidin-2-on, through compounds of formulas III-IV.

COPYRIGHT: (C)1993,JPO

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION This invention relates to carbapenem species antibacterial agents wherein the 2-position side chain is characterized by a 2-phenyl moiety substituted with various substituents, as described in more detail below. ..

[0002]

BACKGROUND OF THE INVENTION Thienamycin is an early carbapenem antibacterial agent with a broad spectrum of antibacterial properties and has the formula:

[0003]

[Chemical 2] Later, N-formimidoyl thienamycin was discovered, which has the formula:

[0004]

[Chemical 3] The 2-phenylcarbapenems of the present invention are not necessarily of interest because of their broad antibacterial spectrum, as is the case with thienamycin or N-formimidoyl thienamycin.
Rather, those areas of activity of primary interest are gram-positive microorganisms, especially methicillin-resistant Staphylococcus aureus Sta.
phylococcus aureus (MRSA),
Methicillin-resistant Staphylococcus epidermidis Staphylococcus
cusepidermidis (MRSE) and methicillin-resistant coagulase-negative Staphylococcus Staphyl
ococci (MRCNS). Therefore, the antimicrobial compounds of the present invention comprise an important contribution to these treatments where pathogen control is difficult. Furthermore, there is an increasing need for agents that are safe at the same time, ie, effective against such pathogens (MRSA / MRCNS) without unwanted toxic side effects. No β-lactam antibacterial agent that satisfies these requirements has been found yet. MRSA / MRCNS pathogens are currently increasing their resistance to vancomycin, which is the latest drug, a glycopeptide antibacterial agent.

More recently, carbapenem antibacterial agents have been described which have a 2-substituent which is an aryl moiety optionally substituted, for example by aminomethyl and substituted aminomethyl. These agents are described in US Pat. Nos. 4,543,257 and 4,260,627 and have the formula:

[0006]

[Chemical 4] However, the surprisingly good anti-MR of the compounds of the invention
There is no description or suggestion of SA / MRCNS activity.

US Pat. No. 4,978,659 has the formula:

[0008]

[Chemical 5] , But in any respect this is a surprisingly good anti-MRS of the compounds of the invention.
It does not indicate A / MRCNS activity.

[0009]

Accordingly, the present invention provides a group of meta-substituted 2-halophenyl carbapenems with unexpected levels of anti-MRSA / MRCNS activity. To be precise, Applicants have found that this unexpected level of activity is due to specific halogen and metaphenyl substitution.

[0010]

The present invention provides the following formula:

[0011]

[Chemical 6] (In the formula, R is H or CH ₃ , and R ² is (R) -CH.
₃ CH (OH)-or (R) -CH ₃ CH (F)-, M is a pharmaceutically acceptable cation or ester, and R ^a is I or Br). provide.

With some sort of 2-side chain selection, the final equilibrium of properties in the whole molecule is 6- (R) (1-hydroxyethyl) instead of 6- (R) (1-hydroxyethyl). It has been found in certain carbapenems that they can be enhanced by selection. 6-within the scope of the present invention
Preparation of fluoroalkyl compounds is carried out in a straightforward manner using techniques well known in the art of preparing carbapenem antibacterial compounds. For example, J. G. deVries et
al. , Heterocycles, 1985, 23,
1915; BE 900 718A (Sandoz),
Also, please refer to JP-A-60-163882 (Sanraku).

In preferred compounds of formula I, R is hydrogen and R ² is 6- (R)-(1-hydroxyethyl). While R = H is usually preferred, there is a case R = CH ₃ is capable of providing chemical stability, water solubility, or improved pharmacokinetic effects. Substituents R = CH ₃ may be of any three-dimensional configuration, i.e. α or β- stereoisomer.

The carbapenem compounds of the present invention are useful in the treatment of bacterial infections in animal and human patients as such, and in their pharmaceutically acceptable salt and ester forms. The term "pharmaceutically acceptable ester or salt" refers to the non-toxic, pharmacokinetic properties of the compounds of the invention which are obvious to the formulation scientist, ie their palatability, absorption, distribution. , Shows salt and ester forms that favorably affect metabolism and excretion. Other factors of practical importance in the selection are raw material cost, ease of crystallization, yield, stability, hygroscopicity and consequent drug powder flowability. The pharmaceutical composition is conveniently prepared from the active ingredients in combination with a pharmaceutically acceptable carrier.
Therefore, the present invention further relates to pharmaceutical compositions and methods for treating bacterial infections using the novel carbapenem compounds of the invention as active ingredients.

The above pharmaceutically acceptable salts are -COOM.
Take the form. M is an alkali metal cation such as sodium or potassium. Other pharmaceutically acceptable cations as M include calcium, zinc, ammonium,
Or an alkylammonium cation such as tetramethylammonium, tetrabutylammonium, choline,
Examples include triethylhydroammonium, meglumine, triethanolhydroammonium and the like.

The pharmaceutically acceptable esters of the novel carbapenem compounds of the present invention are such that they will be readily apparent to the pharmacist, for example, US Pat. No. 4,309,438 column 9 61 line to column 12
51, line 51, and the description thereof is included in the present invention by reference. Included in such pharmaceutically acceptable esters are those that are hydrolyzed under physiological conditions, such as pivaloyloxymethyl, acetoxymethyl, phthalidyl, indanyl, and methoxymethyl, as well as US Pat. 47
No. 9,947 (the contents of which are included in the present invention by reference).

[0017]

The compounds of the present invention are valuable antibacterial agents active against various Gram-positive bacteria and, to a lesser extent, against Gram-negative bacteria and are therefore useful in human and veterinary medicine. is there. The antibacterial agents of the present invention are not limited to medicinal utility; they are used in all types of industries, such as animal feed additives, food preservatives, antiseptics, and other industrial systems where control of bacterial growth is desirable. Can be used for. For example, to eradicate or prevent the growth of harmful bacteria on medical and dental equipment, as well as for industrial applications, for example in water-based paints to prevent the growth of harmful bacteria and in the white water of paper machines. As a bactericide therein, it may be used in the aqueous composition at concentrations ranging from 0.1 to 100 parts of antibacterial agent per million parts of solution.

The compounds of the present invention can be used in any of a variety of formulations. They can be used in capsules, in powder form, in solution or in suspension. They can be administered topically or parenterally, for example by injection (intravenously or intramuscularly), mainly by various means.

Compositions for injection, which is the preferred route of delivery, are prepared in unit dosage form in ampoules or in multi-dose containers. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and contain the formulation. Alternatively, the active ingredient is in powder form for reconstitution with a suitable vehicle, such as sterile water, at the time of delivery. Topical applications include ointments, creams,
It may be formulated as a lotion, paint, or powder in a hydrophobic or hydrophilic base.

The dosage will vary widely depending on the condition and size of the subject being treated and the route and frequency of administration.
The parenteral route by injection is preferred for common infections. However, such matters are at the discretion of the therapist according to therapeutic principles well known in the antimicrobial industry. In addition to the nature and individual variability of the infection of the individual being treated, another factor affecting the precise dosing regimen is the molecular weight of the selected species of the invention.

The human composition per unit dose, whether liquid or solid, is 0.1% to 99%, preferably about 10%.
It contains an active substance in the range of -60%. The compositions generally contain from about 15 mg to about 1500 mg of the active ingredient; however, generally from about 250 mg to 1000 m
It is preferred to use doses in the range of g. For parenteral administration, the unit dose is usually pure Compound I in a sterile aqueous solution or in the form of a soluble powder instead of a solution.

The preferred method of administration of the Formula I antimicrobial compound is parenteral administration by intravenous infusion, intravenous bolus, or intramuscular injection.

For adults, it is preferred to give 5-50 mg of Formula I antibacterial compound / kg body weight 2, 3 or 4 times daily. The preferred administration is twice daily (b.i.
d. ), 3 times (ti.d.), or 4 times (q.i.d.).
d. ) Is 250 mg to 1000 mg of Formula I antibacterial agent. Furthermore, for mild infection, 250 mg t. i.
d. Or q. i. d. A dose of is recommended. 500 mg for moderate infection of highly sensitive Gram-positive organisms
t. i. d. Or q. i. d. A dose of is recommended.
For severe lethal infections of the organism with an upper limit of susceptibility to antibiotics, 1000 mg t. i. d. Or q. i. d. A dose of is recommended.

For children, 5-25 mg / kg body weight
Is preferably given 2, 3, or 4 times daily. Usually 10 mg / kg t. i. d. Or q. i. d. It is good to say

The antibacterial compound of formula I is carbapenem or 1
Of the type widely known as carbadethiapenem. Natural carbapenem is dehydropeptidase (DH
It is susceptible to invasion by the renal enzyme known as P). This invasion or degradation reduces the efficacy of carbapenem antibacterial agents. On the other hand, the compounds of the present invention are significantly less susceptible to such invasion and therefore do not require the use of DHP inhibitors. However, such use is optional and is considered part of this invention. Inhibitors of DHP and their use with carbapenem antibacterial agents have been disclosed in the prior art [European Patent Application No. 79102616.4 filed July 24, 1979 (European Patent No. 0007,614). No.); and 82107174.3 (European Patent No. 0,0) filed on August 9, 1982.
72,014)].

The compounds of the present invention may be combined with or used in combination with a suitable DHP inhibitor as described in the above patents or publications when DHP inhibition is desired or necessary. Therefore, the European patent cited is 1. 2.) Define a procedure for measuring the DHP sensitivity of the present carbapenem, and 2. ) To the extent that suitable inhibitors, combination compositions, and methods of treatment are disclosed, they are incorporated herein by reference. The preferred weight ratio of Formula I compound: DHP inhibitor in the combination composition is about 1: 1. A preferred DHP inhibitor is 7- (L-2-amino-
2-carboxyethylthio) -2- (2,2-dimethylcyclopropanecarboxamido) -2-heptenoic acid or a useful salt thereof.

[0027]

【Example】

 Example 1 Step (a)

[0028]

[Chemical 7] (3S, 4R) -1-[[(allyloxy) carbonyl] (triphenylphosphoranylidene) methyl] -3-
Preparation of [(1R) -1- (allyloxycarbonyloxy) ethyl] -4-[[[(3-bromo) phenyl] carbonyl] methyl] azetidin-2-one: Magnesium (264 mg, 11 mM) in 20 mL It was added to a solution of 1,3-dibromobenzene (2.36 g, 10 mM) dissolved in anhydrous tetrahydrofuran. ~ 8 μL
1,2-dibromoethane was added. After stirring at room temperature under nitrogen for 2 hours, most of the metal was digested and the resulting solution was used as a 0.5 molar solution of 3-bromophenylmagnesium bromide.

This Grignard solution (8 mL) was dissolved in 5 mL of tetrahydrofuran at 0 ° C. under nitrogen.
4 g (2 mM) of (3S, 4R) -1-[[(allyloxy) carbonyl] (triphenylphosphoranylidene)
Methyl] -3-[(1R) -1- (allyloxycarbonyloxy) ethyl] -4-[(1R) -2 ′-[(pyridylthio) carbonyl] methyl] azetidin-2-one was added dropwise to the solution. After 15 minutes, 10 mL of saturated ammonium chloride solution was added, diluted with 25 mL of ethyl acetate and washed with 3 × 10 mL of saturated sodium chloride solution. After dehydration over anhydrous magnesium sulfate, the solvent was removed from the organic phase to produce a crude oil (yellow), which was chromatographed on silica gel with a 2: 3 mixture of ethyl acetate: hexane to give 720 mg. To give the desired ilide ketone as a creamy colored foam.

Step (b)

[0031]

[Chemical 8] (5R, 6S) -2- [3-Bromophenyl] -6-
[(1R) -allyloxycarbonyloxyethyl]-
Preparation of allyl carbapen-2-em-3-carboxylate:
Ylide ketone (650 mg) from step (a) above dissolved in 4 mL of p-xylene, and 2 of hydroquinone.
The solution of individual microcrystals was heated at 130 ° C. for 3 hours in nitrogen. After cooling the reaction mixture, it was applied onto a silica gel column packed with hexane. The column was eluted first with hexane and then with a 1: 3 mixture of ethyl acetate: hexane to give 300 mg of the desired carbapenem as a colorless oil.

Step (c)

[0033]

[Chemical 9] (5R, 6S) -2- [3-Bromophenyl] -6-
Preparation of sodium [(1R) -hydroxyethyl] -carbapene-2-em-3-carboxylate: dissolved in 5 mL of a 1: 1 solution of CH ₂ Cl ₂ : ether in a centrifuge tube in N ₂ at 0 ° C. In a stirred solution of bis-allyl carbapenem (225 mg, 0.4727 mM) of step (b), 2-
Ethylhexanoic acid (75 μL, 0.472 mM), triphenylphosphine (33 mg, 0.135 mM), tetrakistriphenylphosphine palladium (84 m
g, 0.075 mM) and sodium 2-ethylhexanoate (78 mg, 0.472 mM) were sequentially added.
After 5 minutes, a bulky precipitate was observed. After stirring for an additional 2 hours, the reaction mixture was diluted with 10 mL of ether.
After centrifugation, the liquid was decanted. The solid was washed with 2 mL ethyl acetate. The resulting solid was dissolved in 2 mL of water, applied onto a 2 × 1000μ reverse phase silica gel plate and eluted with a 1: 4 mixture of acetonitrile and water. U. V. Scrape active area, 10 mL 4: 1
Stirred with CH ₃ CN: water mixture. The solid was filtered off and washed with 2 x 4 mL of the same solvent. The filtrate is 4 × 25
Wash with mL of hexane, concentrate to ~ 2 mL and lyophilize to give 104 mg of the desired sodium salt as a white fluff.

Example 2 Step (a)

[0035]

[Chemical 10] (3S, 4R) -1-[[(allyloxy) carbonyl] (triphenylphosphoranylidene) methyl] -3-
[(1R) -1- (allyloxycarbonyloxy) ethyl] -4-[[[3-iodophenyl] carbonyl]
Preparation of methyl] azetidin-2-one: n-butyllithium solution (2.5M; 2.1 mL; 5.25 mM)
M-Diiodobenzene (1.65 g; 5 m) dissolved in 10 mL of dry tetrahydrofuran at -78 ° C in nitrogen.
M) was added dropwise to the stirred suspension. After stirring for 10 minutes, 40 mL
264 mg (11
mM magnesium) and a solution of magnesium bromide prepared from 872 μL (10 mM) 1,2-dibromoethane was added dropwise over 10 minutes. The reaction mixture is -7
The mixture was stirred at 8 ° C for 15 minutes and at 0 ° C for 30 minutes. The resulting solution was used as a 0.1 molar solution of m-iodophenyl magnesium bromide.

This solution was added slowly to a solution of 704 mg (1 mM) of pyridyl thioester as described in step (a) of Example 1 to give 400 mg of the desired iridoketone as a light yellow foam.

Step (b)

[0038]

[Chemical 11] (5R, 6S) -2- [3-Iodophenyl] -6-
[1R- (allyloxy) carbonyloxyethyl]-
Preparation of allyl carbapen-2-em-3-carboxylate:
This carbapenem was prepared from the iridoketone of step (a) of this example using the procedure of step (b) of example 1.

Step (c)

[0040]

[Chemical 12] (5R, 6S) -2- [3-Iodophenyl] -6-
[(1R) -1-hydroxyethyl] -carbapene-2
Preparation of sodium em-3-carboxylate: This sodium salt was prepared from the bis-allyl protected carbapenem of step (b) of this example using the procedure of step (c) of this example.

Comparative Example The comparative compound of Table VII was prepared similarly to the compounds of Examples 1 and 2 and the characterization data are reported in Tables I-VI. In particular, comparative 2-fluorophenyl, 2-chlorophenyl, and 2-bromophenyl compounds were made as in Example 1 from the appropriate Grignard reagent. Similarly, 2-
The iodophenyl compound was prepared from the diiodo compound in Example 2.
Generated in the same way.

Characteristic data

[0043]

[Chemical 13]

[0044]

[Table 1]

[0045]

[Table 2]

[0046]

[Chemical 14]

[0047]

[Table 3]

[0048]

[Chemical 15]

[0049]

[Table 4]

[0050]

[Table 5]

[0051]

[Chemical 16]

[0052]

[Table 6] Biological data The activity of the following compounds was measured against a strain of the MRSA pathogen and is described below in the form of efficacy with thienamycin as 1. For this measure of activity see R.S. Guthikon
da, et al. J. Med. Chem. , 30,
871 (1987).

[0053]

[Chemical 17]

[0054]

[Table 7]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Internal reference number FI technical display location A61K 31: 195) 8413-4C (72) Inventor Ravindra N. Gutai Conda New Jersey 08820 USA , Edison, Savoy Avenir 289

Claims (9)

[Claims] 1. The following formula: (In the formula, R is H or CH ₃ , and R ² is (R) -CH.
₃ CH (OH) - or _{(R) -CH 3 CH (F} ) - a and, M is a pharmaceutically acceptable cation or ester, compound of R ^a is I or Br). 2. The compound according to claim 1, wherein R ² is (R) —CH ₃ CH (OH) — and R is H. 3. The compound according to claim 1, wherein M is sodium or potassium ion. 4. A pharmaceutically acceptable carrier and 0.1% by weight.
A composition comprising about 99% by weight of the active substance of claim 1. 5. The composition according to claim 4, further comprising an inhibitory effective amount of a DHP inhibitor. 6. The method according to claim 5, wherein the DHP inhibitor is 7- (L-2-amino-2-carboxyethylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptanoic acid. Composition. 7. A method of treating a bacterial infection in a mammal comprising administering an effective amount of a pharmaceutical composition containing the compound of claim 1 and a pharmaceutically acceptable carrier thereof. 8. The method of claim 7, further comprising administering an inhibitory effective amount of a DHP inhibitor. 9. The method according to claim 8, wherein the DHP inhibitor is 7- (L-2-amino-2-carboxyethylthio) -2- (2,2-dimethylcyclopropanecarboxamide) -2-heptanoic acid. Method.